ROCURONIUM Drug Interactions: What You Need to Know

INTERACTIONS Succinylcholine : Use before succinylcholine has not been studied. ( 7.11 ) Nondepolarizing muscle relaxants : Interactions have been observed. ( 7.7 )

Enhanced Rocuronium Bromide

Injection activity possible : Inhalation anesthetics ( 7.3 ), certain antibiotics ( 7.1 ), quinidine ( 7.10 ), magnesium ( 7.6 ), lithium ( 7.4 ), local anesthetics ( 7.5 ), procainamide ( 7.8 )

Reduced Rocuronium Bromide

Injection activity possible : Anticonvulsants. ( 7.2 )

7.1 Antibiotics Drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as Rocuronium Bromide Injection include certain antibiotics (e.g., aminoglycosides; vancomycin; tetracyclines; bacitracin; polymyxins; colistin; and sodium colistimethate). If these antibiotics are used in conjunction with Rocuronium Bromide Injection, prolongation of neuromuscular block may occur.

7.2 Anticonvulsants In 2 of 4 patients who received chronic anticonvulsant therapy, apparent resistance to the effects of another rocuronium bromide injection product was observed in the form of diminished magnitude of neuromuscular block or shortened clinical duration. As with other nondepolarizing neuromuscular blocking drugs, if Rocuronium Bromide Injection is administered to patients chronically receiving anticonvulsant agents such as carbamazepine or phenytoin, shorter durations of neuromuscular block may occur and infusion rates may be higher due to the development of resistance to nondepolarizing muscle relaxants. While the mechanism for development of this resistance is not known, receptor up-regulation may be a contributing factor <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.10 )]</span> .

7.3 Inhalation Anesthetics Use of inhalation anesthetics (enflurane &gt; isoflurane &gt; halothane) has been shown to enhance the activity of other neuromuscular blocking agents. Isoflurane and enflurane may also prolong the duration of action of initial and maintenance doses of Rocuronium Bromide Injection and decrease the average infusion requirement of Rocuronium Bromide Injection by 40% compared to opioid/nitrous oxide/oxygen anesthesia. No definite interaction between rocuronium bromide injection and halothane has been demonstrated. In one study, use of enflurane in 10 patients who received another rocuronium bromide injection product resulted in a 20% increase in mean clinical duration of the initial intubating dose, and a 37% increase in the duration of subsequent maintenance doses, when compared in the same study to 10 patients under opioid/nitrous oxide/oxygen anesthesia. The clinical duration of initial doses of another rocuronium bromide injection product (0.57 to 0.85 mg/kg) under enflurane or isoflurane anesthesia, as used clinically, was increased by 11% and 23%, respectively. The duration of maintenance doses was affected to a greater extent, increasing by 30% to 50% under either enflurane or isoflurane anesthesia. Potentiation by these agents was also observed with respect to the infusion rates of rocuronium bromide injection required to maintain approximately 95% neuromuscular block. Under isoflurane and enflurane anesthesia, the infusion rates were decreased by approximately 40% compared to opioid/nitrous oxide/oxygen anesthesia. The median spontaneous recovery time (from 25% to 75% of control T1) was not affected by halothane but is prolonged by enflurane (15% longer) and isoflurane (62% longer). Reversal-induced recovery of Rocuronium Bromide Injection neuromuscular block is minimally affected by anesthetic technique <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 ) and Warnings and Precautions ( 5.10 )]</span> .

7.4 Lithium Carbonate Lithium has been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.10 )]</span> .

7.5 Local Anesthetics Local anesthetics have been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.10 )]</span> .

7.6 Magnesium Magnesium salts administered for the management of pre-eclampsia or eclampsia of pregnancy may enhance neuromuscular blockade <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.10 )]</span> .

7.7 Nondepolarizing Muscle Relaxants There are no controlled studies documenting the use of Rocuronium Bromide Injection before or after other nondepolarizing muscle relaxants. Interactions have been observed when other nondepolarizing muscle relaxants have been administered in succession.

7.8 Procainamide Procainamide has been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.10 )]</span> .

7.9 Propofol The use of propofol for induction and maintenance of anesthesia does not alter the clinical duration or recovery characteristics following recommended doses of Rocuronium Bromide Injection.

7.10 Quinidine Injection of quinidine during recovery from use of muscle relaxants is associated with recurrent paralysis. This possibility must also be considered for Rocuronium Bromide Injection <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.10 )]</span> .

7.11 Succinylcholine The use of Rocuronium Bromide Injection before succinylcholine, for the purpose of attenuating some of the side effects of succinylcholine, has not been studied.

If Rocuronium Bromide

Injection is administered following administration of succinylcholine, it should not be given until recovery from succinylcholine has been observed. The median duration of action of Rocuronium Bromide Injection 0.6 mg/kg administered after a 1 mg/kg dose of succinylcholine when T1 returned to 75% of control was 36 minutes (range: 14-57, n=12) vs. 28 minutes (range: 17-51, n=12) without succinylcholine.

Rocuronium bromide injection is contraindicated in patients known to have hypersensitivity (e.g., anaphylaxis) to rocuronium bromide or other neuromuscular blocking agents [see Warnings and Precautions ( 5.2 )] .

• Hypersensitivity (e.g., anaphylaxis) to rocuronium bromide or other neuromuscular blocking agents. ( 4 )

AND PRECAUTIONS Appropriate Administration and Monitoring : Use only if facilities for intubation, mechanical ventilation, oxygen therapy, and an antagonist are immediately available. ( 5.1 ) Anaphylaxis : Severe anaphylaxis has been reported. Consider cross-reactivity among neuromuscular blocking agents. ( 5.2 ) Risk of Death due to Medication Errors : Accidental administration can cause death. ( 5.3 ) Need for Adequate Anesthesia : Must be accompanied by adequate anesthesia or sedation. ( 5.4 )

Residual

Paralysis : Consider using a reversal agent in cases where residual paralysis is more likely to occur. ( 5.5 )

5.1 Appropriate Administration and Monitoring Rocuronium bromide injection should be administered in carefully adjusted dosages by or under the supervision of experienced clinicians who are familiar with the drug&apos;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 rocuronium bromide 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.

5.2 Anaphylaxis Severe anaphylactic reactions to neuromuscular blocking agents, including rocuronium bromide, have been reported. These reactions have, in some cases (including cases with rocuronium bromide), 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.

5.3 Risk of Death due to Medication Errors Administration of rocuronium bromide injection results in paralysis, which may lead to respiratory arrest and death, a progression that may be more likely to occur in a patient for whom it is not intended. Confirm proper selection of intended product and avoid confusion with other injectable solutions that are present in critical care and other clinical settings. If another healthcare provider is administering the product, ensure that the intended dose is clearly labeled and communicated. Administration of rocuronium bromide injection results in paralysis, which may lead to respiratory arrest and death, a progression that may be more likely to occur in a patient for whom it is not intended. Confirm proper selection of intended product and avoid confusion with other injectable solutions that are present in critical care and other clinical settings. If another healthcare provider is administering the product, ensure that the intended dose is clearly labeled and communicated.

5.4 Need for Adequate Anesthesia Rocuronium bromide has no known effect on consciousness, pain threshold, or cerebration. Therefore, its administration must be accompanied by adequate anesthesia or sedation.

5.5 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. Geriatric patients (65 years or older) may be at increased risk for residual 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.

5.6 Long-Term Use in an Intensive Care Unit Rocuronium bromide has not been studied for long-term use in the intensive care unit (ICU). As with other nondepolarizing neuromuscular blocking drugs, apparent tolerance to rocuronium bromide 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 rocuronium bromide 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.

5.7 Malignant Hyperthermia (MH) Rocuronium bromide has not been studied in MH-susceptible patients. Because rocuronium bromide 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . In an animal study in MH-susceptible swine, the administration of rocuronium bromide injection did not appear to trigger malignant hyperthermia.

5.8 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 )]</span> .

5.9 QT Interval Prolongation The overall analysis of ECG data in pediatric patients indicates that the concomitant use of rocuronium bromide with general anesthetic agents can prolong the QTc interval <span class="opacity-50 text-xs">[see Clinical Studies ( 14.3 )]</span>.

5.10 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.3 )]</span> . 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 rocuronium bromide should be considered <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 )]</span> .

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 rocuronium bromide 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 rocuronium bromide. No data are available in such patients and no dosing recommendations can be made. Rocuronium bromide-induced neuromuscular blockade was modified by alkalosis and acidosis in experimental pigs. Both respiratory and metabolic acidosis prolonged the recovery time. The potency of rocuronium bromide 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.

5.11 Incompatibility with Alkaline Solutions Rocuronium bromide injection, 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.

5.12 Increase in Pulmonary Vascular Resistance Rocuronium bromide injection may be associated with increased pulmonary vascular resistance, so caution is appropriate in patients with pulmonary hypertension or valvular heart disease <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 )]</span> .

5.13 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.

5.14 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.