ROCURONIUM BROMIDE

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Accidental administration of neuromuscular blocking agents can be fatal. Store rocuronium with the cap and ferrule intact, in a manner that minimizes the possibility of selecting the wrong product.
-Updates for coronavirus disease 2019 (COVID-19): The FDA is allowing rocuronium 50 mg/5 mL and 100 mg/10 mL to be used beyond the labeled in-use time to help ensure access during COVID-related drug shortages. This period should be as short as possible, and for a maximum of 2 hours at room temperature or 4 hours when refrigerated. In-use time is defined as the maximum amount of time allowed to elapse between penetration of a closed-container system or after reconstitution of a lyophilized drug before patient administration.
Intravenous Administration
-Only experienced clinicians, familiar with the use of neuromuscular blocking drugs, should administer or supervise the use of rocuronium. Adequacy of respiration must be assured through assisted or controlled ventilation.
-To avoid distress to the patient, administer rocuronium only after unconsciousness has been induced. Adequate amnesia, sedation, and analgesia should accompany neuromuscular blockade.
-Do not mix rocuronium with alkaline solutions (e.g., barbiturate solutions such as thiopental) in the same syringe or administer simultaneously during IV infusion through the same needle or through the same IV line; rocuronium has an acidic pH.
-If extravasation occurs, stop the injection or infusion and restart in another vein.

Intermittent IV Injection
-No further dilution necessary.
-Administer by direct IV injection over 5 to 10 seconds.

Continuous IV Infusion
-Dilute with 0.9% Sodium Chloride Injection, 5% Dextrose Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, Lactated Ringer's Injection, or Sterile Water for Injection to a concentration up to 5 mg/mL.
-Infuse at rate based on patient response and requirements.
-A peripheral nerve stimulator is recommended to monitor rocuronium's effects. Target response is typically 1 to 2 twitches. Incorrect electrode placement, direct stimulation of muscle due to large electrode size, acute illness, capillary leak, and edema may affect an appropriate assessment. Monitor visual and tactile stimulation on muscle movement as well as heart rate, blood pressure, and mechanical ventilator status during administration.
-Storage: Diluted solutions may be stored at room temperature for up to 24 hours in plastic bags, glass bottles, and plastic syringe pumps.

Intramuscular Administration
NOTE: Rocuronium is not FDA-approved for intramuscular administration.
-Not recommended. In children 3 months to 5 years, a rapid single bolus into the deltoid muscle has been studied; adequate intubating conditions were not consistently obtained.

Asthma (bronchospasm, wheezing, or rhonchi) and hiccups were reported in less than 1% of patients receiving rocuronium during clinical trials.

Rocuronium is associated with fewer cardiac adverse events compared to some other neuromuscular blocking agents. Transient hypotension and hypertension (2%) were the most common adverse reactions reported during European clinical trials (n = 1,394). These reactions were reported in 0.1% of patients during US trials (n = 1,137) where changes in blood pressure and heart rate were not considered adverse unless they were judged to be unexpected, clinically significant, or histamine-related. Arrhythmias, abnormal electrocardiogram (ECG), and sinus tachycardia were reported in less than 1% of patients receiving rocuronium during clinical trials. In worldwide pediatric studies (n = 704), rocuronium-related sinus tachycardia occurred in 1.4% of patients. Of children 3 months to 14 years who were anesthetized with halothane and did not receive atropine for induction, 80% had a transient increase in heart rate of at least 30% after intubation. In contrast, 1 of 19 infants (0.05%) anesthetized with halothane and fentanyl who received atropine for induction experienced heart rate fluctuations of the same magnitude. Data from pediatric trials with sevoflurane induction and isoflurane/nitrous oxide maintenance anesthesia also suggest rocuronium may cause tachycardia. Tachycardia may result from the vagal blocking activity of rocuronium; animal data suggest that the ratio of vagal:neuromuscular block with rocuronium is less than vecuronium but greater than pancuronium. Overall ECG data suggests concomitant use of rocuronium with general anesthesia may cause QT prolongation; however, rocuronium has not been identified independently of anesthesia and/or other related factors.

Although rare, severe anaphylactic or anaphylactoid reactions to neuromuscular blocking agents (NMBAs), including rocuronium, have been reported; some cases have been fatal. Immediate availability of appropriate emergency treatment for anaphylaxis is advised because of the potential life-threatening severity of a reaction. Rocuronium has minimal histamine-release at therapeutic doses and is less likely to cause bronchospasm or cardiac adverse effects than NMBAs with significant histamine-releasing properties such as atracurium, mivacurium, or succinylcholine. However, rare hypersensitivity reactions (e.g., angioedema, bronchospasm, wheezing, flushing, rash, erythema, urticaria, pruritus, hypotension, sinus tachycardia) related to histamine release have been reported after rocuronium administration.

Malignant hyperthermia can be precipitated by many drugs used in anesthetic practice, including halogenated anesthetics and depolarizing neuromuscular blocking agents (e.g., succinylcholine). It is unknown whether rocuronium is capable of triggering hyperthermia; however, because of the potentially fatal outcome, consider all patients undergoing anesthesia with administration of neuromuscular blocking agents, such as rocuronium, at risk.

Rocuronium is used for the purpose of inducing temporary paralysis; however, some of its most serious adverse effects are extensions of its therapeutic use. Careful monitoring of physiologic parameters and response to a peripheral nerve stimulator is recommended during continuous infusions or repeated dosing. Though paralysis may be used to facilitate mechanical ventilation, hypoxia may result from inadequate ventilation and/or a deterioration in pulmonary mechanics associated with prolonged paralysis. Excessive doses or prolonged exposure to neuromuscular blocking agents (NMBAs) can cause skeletal muscle weakness, and patients may consequentially experience prolonged apnea, dyspnea, respiratory depression, and/or profound muscular weakness (muscle paralysis). Muscle weakness in critically ill patients is multifactorial; however, prolonged recovery is most often related to excessive dosing of neuromuscular blockers or use of these agents in patients with hepatic or renal dysfunction. These patients may take hours to days to recover due to long-term accumulation of the drug and its metabolites. Perhaps the most devastating complication of neuromuscular blockade, acute quadriplegic myopathy syndrome (AQMS), presents as acute paresis, myonecrosis with increased creatine phosphokinase (CPK), and abnormal electromyography (EMG). After drug discontinuation, patients present with flaccid paralysis, decreased deep tendon reflexes, and respiratory insufficiency. Sensory function and extraocular movement are preserved, and there are no abnormal cerebrospinal fluid findings. Prolonged rehabilitation as well as chronic ventilatory support are often needed in patients with AQMS. Recovery may take weeks to months. To reduce the risk of prolonged recovery and AQMS, periodic screening of CPK during ongoing neuromuscular blockage may be helpful. Though periodic interruption of therapy is often not feasible and there is no direct evidence showing that it reduces the incidence of AQMS, daily 'drug holidays' may be considered for patients who will tolerate an interruption in therapy.

Patients receiving rocuronium are at risk for developing xerophthalmia, leading to keratitis, conjunctivitis, and corneal abrasion because muscle paralysis inhibits eyelid movement and complete closure. Prophylactic eye care is essential; use artificial tears or ophthalmic ointment at regular intervals during neuromuscular blockade. Additionally, paralyzed patients with prolonged immobility are at risk for skin erosion, skin ulcer (pressure sore), and deep vein thrombosis (DVT). Frequent repositioning, physical therapy, and sequential compression devices (if age appropriate) are indicated. The use of special mattresses may be considered.

Rocuronium may exacerbate pulmonary hypertension due to its effects on pulmonary vascular resistance. Rocuronium was associated with transient increases (30% or more) in pulmonary vascular resistance in some adult patients with clinically significant cardiovascular disease undergoing coronary artery bypass graft. Transient increases of the same magnitude were also observed in 24% of adult patients who received rocuronium (0.6 or 0.9 mg/kg/dose) during abdominal aortic surgery.

Awake, paralyzed patient-anxiety and panic may be the most bothersome adverse effect associated with neuromuscular blockade. Neuromuscular blockers, such as rocuronium, do not provide sedation or analgesia and should be administered only after unconsciousness has been induced. It is essential that amnesia, sedation, and analgesia are adequately maintained throughout paralyzation. Depth of sedation is difficult to monitor due to lack of movement with paralyzation. Physiologic parameters such as heart rate or blood pressure may be of use; however, there are many confounding influences on these parameters in critically ill patients.

Patients who receive neuromuscular blocking agents for a prolonged period may develop tachyphylaxis (i.e., tolerance). Prolonged blockade leads to proliferation of acetylcholine receptors at the neuromuscular junction resulting in increased drug requirements. Switch patients who develop tachyphylaxis to rocuronium and still require neuromuscular blockade to another agent. Continuous monitoring of neuromuscular transmission with a peripheral nerve stimulator is strongly recommended during continuous infusion or repeated dosing. Target response is typically 1 to 2 twitches. Incorrect electrode placement, direct stimulation of muscle due to large electrode size, acute illness, capillary leak, and edema may affect an appropriate assessment. Monitor visual and tactile stimulation on muscle movement as well as heart rate, blood pressure, and mechanical ventilator status during administration.

Nausea and vomiting were reported in less than 1% of patients receiving rocuronium during clinical trials.

An injection site reaction, specifically edema, was reported in less than 1% of patients receiving rocuronium during clinical trials. If extravasation occurs, it may be associated with local irritation. Stop the injection or infusion and restart in another vein.

Administer rocuronium only after unconsciousness has been induced; maintain adequate amnesia and analgesia throughout paralyzation. Neuromuscular blocking agents do not cause sedation or analgesia. Individualize rocuronium doses. Use of a peripheral nerve stimulator will permit the most advantageous use of rocuronium, minimize the possibility of overdosage or underdosage, and assist in the evaluation of recovery.

Rocuronium administration requires an experienced clinician who is familiar with its actions and the possible complications that may occur after its use as well as requires a specialized care setting where facilities for intubation, artificial respiration, oxygen therapy, and reversal agents are immediately available. Accidental exposure to a neuromuscular blocking agent may be fatal in a patient for whom it is not intended. Store rocuronium with cap and ferrule intact and in a manner that minimizes the possibility of selecting the wrong product. Confirm proper medication selection and clearly communicate the intended dose.

Rocuronium is contraindicated in patients known to have a rocuronium bromide hypersensitivity or other neuromuscular blocking agent hypersensitivity. Cross-reactivity between neuromuscular blocking agents, both depolarizing and non-depolarizing, has been reported. Severe anaphylactic reactions to neuromuscular blocking agents, including rocuronium, have been reported. These reactions have been life-threatening and fatal in some cases. Due to the potential severity of these reactions, ensure the necessary precautions, such as the immediate availability of appropriate emergency treatment.

Patients with burns have a decreased sensitivity to rocuronium's ability to produce neuromuscular blockade. Resistance to blockade usually develops in patients with burns more than 10% total body surface area approximately 1 week after thermal injury. Increased doses may be required in burn patients; alteration in drug effect may be seen for up to 1 year. In patients with more than 40% total body surface area burns, significant increases in dosage requirements (i.e., 2.5 to 5 times the usual dose) have been reported.

Various physiologic states can alter the expected effects of rocuronium; carefully consider each patient's clinical condition when dosing rocuronium and monitoring the patient. Cachectic and debilitated patients are more sensitive to neuromuscular blocking agents (NMBAs). Electrolyte imbalance can alter a patient's sensitivity to NMBAs. Hypercalcemia can decrease sensitivity to NMBAs, while most other electrolyte disturbances increase sensitivity (e.g., hypokalemia, hypocalcemia, hypermagnesemia). Use rocuronium cautiously in patients with conditions that may lead to electrolyte imbalances, such as adrenal insufficiency. Severe acid/base imbalance may alter a patient's sensitivity to NMBAs: metabolic alkalosis, metabolic acidosis, and respiratory acidosis may enhance neuromuscular blockade and/or prolong recovery time, while respiratory alkalosis reduces the potency of the drug. Dehydration and hypothermia can also increase a patient's sensitivity to NMBAs.

Use neuromuscular blocking agents (NMBAs) with caution in patients with asthma or other pulmonary conditions. NMBAs stimulate histamine release, which could exacerbate asthma. Compared with other NMBAs, rocuronium produces little or no histamine release. While some experts consider rocuronium to be an NMBA of choice in asthmatic patients, it should be used with caution in those with any condition in which a release of histamine may be contraindicated. Also, NMBAs cause respiratory muscle paralysis; residual muscle weakness and decreased respiratory function can persist even after drug discontinuation. Use NMBAs with caution in patients with pulmonary disease and conditions associated with low pulmonary function reserve, such as neonatal chronic lung disease (CLD). Carefully monitor respiratory status and adequacy of ventilation after drug recovery until the patient is clearly stabilized.

Use rocuronium with caution in patients with neuromuscular disease (e.g., myasthenia gravis, myasthenic syndrome [Eaton Lambert syndrome]); prolonged or exaggerated neuromuscular blockade may occur after nondepolarizing agent use. Additionally, patients with weak muscle tone or severe obesity are at an increased risk for airway and ventilation complications. Consider the use of a small test dose and a peripheral nerve stimulator to monitor response in these patients. Monitor patients carefully until recovery is fully complete. Guidelines for sustained neuromuscular blockade in critically ill children recommend calculating the dose according to IBW.

Use rocuronium with caution in patients with cardiac disease or other conditions that may be associated with a slower circulation time. Changes in the volume of distribution related to poor circulation or edema can delay the onset of neuromuscular blockade. Particular care is required in administering subsequent doses when it is uncertain whether maximum effect has been attained.

Use rocuronium with caution in patients with clinically significant hepatic impairment; patients with hepatic disease may experience prolonged recovery time. In patients with ascites, an increased initial dosage may be required to achieve adequate neuromuscular blockade. Duration will be prolonged in these cases.

Patients with renal failure may have a more variable duration of effect.

Treat patients with a personal or familial history of malignant hyperthermia with extreme caution. Malignant hyperthermia can be precipitated by many drugs used in anesthetic practice, including halogenated anesthetics and depolarizing neuromuscular blocking agents (e.g., succinylcholine). It is unknown whether rocuronium is capable of triggering hyperthermia.

Use rocuronium with caution in patients with pulmonary hypertension or valvular heart disease because it has been associated with transient increases pulmonary vascular resistance.

Analysis of ECG data in pediatric patients suggests concomitant use of rocuronium with general anesthesia (i.e., halothane, sevoflurane, isoflurane, and nitrous oxide) may cause QT prolongation. Use rocuronium in combination with general anesthetics with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving other medications known to prolong the QT interval or cause electrolyte imbalances. Females, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.

Neonates and infants are more sensitive to the effects of rocuronium compared to older patients; they may take longer to recover from neuromuscular blockade. Monitor young patients carefully during and after administration.

Description: Rocuronium is a parenteral, intermediate-acting, nondepolarizing, neuromuscular blocking agent (NMBA) indicated as an adjunct to general anesthesia to facilitate both rapid-sequence and routine tracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation. Rocuronium is an analog of vecuronium, developed out of the need for an agent with a rapid onset and short duration of action, as well as a low risk of side effects. Although generally considered an intermediate-acting agent, at larger doses, the onset of action shortens. Rocuronium's onset of action is comparable to that of succinylcholine, and it is often considered an alternative for rapid sequence intubation (RSI). Its duration of action is significantly longer than succinylcholine. Rocuronium produces minimal histamine release and is less likely to cause bronchospasm or cardiac adverse effects than neuromuscular blockers with significant histamine-releasing properties such as succinylcholine or atracurium. While continuous infusions of neuromuscular blocking agents are often used in critically ill adults, the use of sustained neuromuscular blockade is less common in pediatric intensive care units. Consensus guidelines from the United Kingdom recommend vecuronium or atracurium as the preferred agents for critically ill children requiring sustained neuromuscular blockade, although strong data comparing neuromuscular blocking agents in pediatric patients are not available. Rocuronium is FDA-approved for use in pediatric patients as young as neonates.

General dosing information:
-Based on physiologic differences, neonates and infants tend to be more sensitive to paralysis with neuromuscular blocking agents, while children tend to require larger doses than those of infants or adults.
-FDA-approved labeling recommends dosing obese patients based on actual body weight (ABW); however, some studies suggest dosing based on ideal body weight (IBW) is associated with a similar onset of paralysis and intubating conditions, with a shorter duration of effect. Guidelines for sustained neuromuscular block in critically ill children recommend calculating the dose according to IBW.
-Use a peripheral nerve stimulator during continuous infusion or repeated dosing to monitor rocuronium's effects. Target response is typically 1 to 2 twitches. Incorrect electrode placement, direct stimulation of muscle due to large electrode size, acute illness, capillary leak, and edema may affect an appropriate assessment. Monitor visual and tactile stimulation on muscle movement as well as heart rate, blood pressure, and mechanical ventilator status during administration.
-Switch patients who develop tachyphylaxis to rocuronium and still require paralysis to another agent.

For muscular relaxation during non-emergent endotracheal intubation:
Intravenous dosage:
Neonates: 0.45 to 0.6 mg/kg/dose IV. Onset of intubating conditions is 1 to 2 minutes. The lower dose of 0.45 mg/kg results in significantly shorter recovery time compared to larger doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Infants, Children, and Adolescents: 0.45 to 0.6 mg/kg/dose IV. Onset of intubating conditions is 60 to 75 seconds. A lower dose of 0.3 mg/kg IV has been used successfully in combination with inhalation anesthesia induction for surgery. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For muscular relaxation during rapid-sequence intubation (RSI)*:
Intravenous dosage:
Neonates: 0.45 to 1.2 mg/kg/dose IV. Onset of intubating conditions is 1 to 2 minutes. Specific recommendations for RSI are not available; doses are extrapolated from use in non-emergent situations. The lower dose of 0.45 mg/kg results in significantly shorter recovery time compared to larger doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Infants, Children, and Adolescents: 0.6 to 1.2 mg/kg/dose IV. Usual dose: 1 mg/kg/dose. Onset of intubating conditions is 1 to 2 minutes. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For neuromuscular blockade during mechanical ventilation in intensive care patients:
Intermittent Intravenous dosage:
Neonates: 0.45 to 0.6 mg/kg IV once, followed by 0.075 to 0.6 mg/kg/dose IV as needed; adjust dose and interval to patient's twitch response. Neonates generally have a lower dosage requirement. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Infants, Children, and Adolescents: 0.45 to 0.6 mg/kg IV once, followed by 0.075 to 0.6 mg/kg/dose IV as needed; adjust dose and interval to patient's twitch response. Children (3 to 11 years) generally have the largest dosage requirement. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Continuous Intravenous Infusion dosage:
Neonates: 0.6 mg/kg IV bolus, followed by 5 to 10 mcg/kg/minute continuous IV infusion; titrate to patient's twitch response. Neonates generally have a lower dosage requirement. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Infants, Children, and Adolescents: 0.6 mg/kg IV bolus, followed by 5 to 10 mcg/kg/minute continuous IV infusion; titrate to patient's twitch response. Children (3 to 11 years) generally have the largest dosage requirement. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For neuromuscular blockade during surgery:
Intermittent Intravenous dosage:
Neonates: 0.45 to 0.6 mg/kg IV once, followed by 0.075 to 0.15 mg/kg/dose IV as needed; adjust dose and interval to patient's twitch response. Neonates generally have a lower dosage requirement. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Infants, Children, and Adolescents: 0.45 to 0.6 mg/kg IV once, followed by 0.075 to 0.15 mg/kg/dose IV as needed; adjust dose and interval to patient's twitch response. Children (3 to 11 years) generally have the largest dosage requirement. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Continuous Intravenous Infusion dosage:
Neonates: 0.45 to 0.6 mg/kg IV bolus, followed by 7 to 12 mcg/kg/minute continuous IV infusion; titrate to patient's twitch response. Neonates generally have a lower dosage requirement. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Infants, Children, and Adolescents: 0.45 to 0.6 mg/kg IV bolus, followed by 7 to 12 mcg/kg/minute continuous IV infusion; titrate to patient's twitch response. Children (3 to 11 years) generally have the largest dosage requirement. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Maximum Dosage Limits:
Specific maximum dosage information is not available. Dosage must be individualized based on clinical response.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in patients with hepatic impairment are not available. Use rocuronium with caution in patients with clinically significant hepatic impairment; patients with hepatic disease may experience prolonged recovery time. In patients with ascites, an increased initial dosage may be required to achieve adequate neuromuscular blockade. Duration will be prolonged in these cases.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available. Patients with renal failure may have a more variable duration of effect.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Muscle contraction is initiated by an action potential traveling from the central nervous system to the nerve terminal. At the nerve terminal, the action potential causes an influx of calcium, initiating the release of acetylcholine (ACh) into the synaptic cleft. ACh binds to ACh receptors on the muscle fiber's motor end-plate causing a conformational change that briefly opens sodium ion channels. When an adequate number of ACh receptors are activated, membrane potential decreases and voltage-dependent sodium ion channels of adjacent muscle membranes activate, transmitting the action potential throughout the muscle fiber and resulting in muscle contraction. Nondepolarizing neuromuscular blocking agents (NMBAs) such as rocuronium produce skeletal muscle paralysis by competing with ACh for cholinergic receptor sites at the motor end-plate. Neuromuscular blockade progresses in a predictable order, beginning with muscles associated with fine movements (e.g., eyes, face, and neck), followed by muscles of the limbs, chest, and abdomen and, finally, the diaphragm. Larger doses increase the chance of respiratory depression associated with relaxation of the intercostal muscles and the diaphragm. Muscle tone returns in the reverse order.

Rocuronium is a monoquaternary aminosteroid. It is an analog of vecuronium and was developed in an attempt to provide an agent with a more rapid onset of action to rival the polarizing agent succinylcholine. It is 10% to 15% as potent as its parent compound. NMBAs do not have the same effects on every muscle group and the onset of laryngeal adductor paralysis is slower with rocuronium compared to succinylcholine. In addition to its therapeutic actions, rocuronium can cause an increase in heart rate, but this is minimal even at large doses. Rocuronium produces little histamine release and no ganglion blockade; therefore, hypotension and bronchospasm are not associated with its use.

Pharmacokinetics: Rocuronium is administered intravenously; although not FDA-approved, the intramuscular route has been studied. Rocuronium is distributed into the extracellular space and not into fat reserves. Protein binding is about 30%. Tissue redistribution accounts for about 80% of the initial dose administered. As tissue compartments fill with continued dosing (4 to 8 hours), less drug is redistributed away from the site of action, and the infusion rate to maintain neuromuscular blockade falls to about 20% of the initial infusion rate. The use of a loading dose and a smaller infusion rate reduces the need for dosage adjustment. Metabolism of rocuronium occurs in the liver. Rarely, the metabolite 17-desacetyl-rocuronium has been detected in human plasma or urine. In animal models, this metabolite is one-twentieth as potent as the parent compound. Data suggest pharmacokinetic parameters are linearly proportional to body weight. In pediatric patients, Vd and clearance increase with body weight and age. The terminal half-life decreases with increasing age from 1.1 hours in neonates to 0.7 to 0.8 hours in older children and adolescents. In comparison, the terminal half-life in healthy adults is approximately 1.4 to 2.4 hours.

Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4
Based on in vitro data, rocuronium is primarily metabolized by CYP3A4.


-Route-Specific Pharmacokinetics
Intravenous Route
Onset time and clinical duration vary with dose, age, and anesthetic technique. After IV administration, plasma concentrations follow a 3-compartment open model; the half-life is 1 to 2 minutes during the rapid distribution phase and 14 to 18 minutes during the slower distribution phase. Larger doses decrease time to maximum effect and prolong the duration of action. In general, maximum neuromuscular effect is seen within 30 to 60 seconds in pediatric patients compared to 60 to 180 seconds in adults. After receipt of 1 mg/kg IV, clinical duration is 53 to 72 minutes for non-neonatal pediatric patients depending on age. Median time to recovery is shortest in children and longest in infants. In general, spontaneous recovery and reversal of neuromuscular blockade after rocuronium infusion discontinuation can be expected to be comparable to that after similar total exposure to single bolus doses. In pediatric patients 3 months and older, time to recovery was shorter after stopping infusion maintenance when compared to bolus maintenance.

Intramuscular Route
Reported bioavailability after IM administration (deltoid muscle) of 14 infants and children (3 months to 5 years) was 82.6% Time to adequate tracheal intubation has varied among studies but is consistently longer than after IV rocuronium and IM succinylcholine administration. In a pilot study of infants and children (n = 29) anesthetized with nitrous oxide and halothane, rocuronium 1 mg/kg IM in infants and 1.8 mg/kg IM in children permitted tracheal intubation at 2.5 to 3 minutes and produced complete paralysis (100% twitch depression) in 7.4 minutes in infants and 6.3 minutes in children. A multicenter, randomized study of infants and children (n = 38, 3 months to 12 years) specifically designed to confirm those results reported inadequate intubating conditions at 3.5 to 4 minutes, with complete paralysis (at least 98% twitch depression) in 7.4 minutes in infants and 8.9 minutes in children. Simulations based on pharmacokinetic parameters suggest a median Tmax of 13 minutes (range: 9 to 19.8 minutes). In infants and children, 25% recovery occurred in 79 minutes and 86 minutes, respectively.


-Special Populations
Pediatrics
Neonates
In general, neonates and infants have a larger extracellular fluid compartment, resulting in a larger Vd compared to children and adults. Mean Vd of rocuronium was 0.42 L/kg with a clearance of 0.31 L/kg/hour and an elimination half-life of 1.1 hours during clinical studies with concurrent sevoflurane induction and isoflurane/nitrous oxide maintenance anesthesia. Although a large Vd could suggest larger dosage requirements, infants have fewer acetylcholine receptors; therefore, plasma concentrations of rocuronium needed to maintain paralysis are lower. In addition, newborns have immature acetylcholine receptors which may result in greater variability in neuromuscular blockade response. In clinical studies with sevoflurane induction and isoflurane/nitrous oxide maintenance anesthesia, the time to maximum block for an intubating dose was longest in neonates; median times for IV doses of 0.45 mg/kg, 0.6 mg/kg, and 1 mg/kg were 1.1 minutes, 1 minute, and 0.6 minutes, respectively. Median duration of action increased with increasing dose and the median ranged from 40 minutes (0.45 mg/kg/dose) to 114 minutes (1 mg/kg/dose).

Infants and Children 1 month to 2 years
In general, neonates and infants have a larger extracellular fluid compartment, resulting in a larger Vd compared to children and adults. Mean Vd of rocuronium was 0.23 to 0.3 L/kg, with a clearance of 0.3 to 0.35 L/kg/hour during clinical studies with concurrent sevoflurane induction and isoflurane/nitrous oxide maintenance anesthesia. Mean elimination half-life varied from 0.8 to 1.3 hours. Although a large Vd could suggest larger dosage requirements, infants have fewer acetylcholine receptors; therefore, plasma concentrations of rocuronium needed to maintain paralysis are lower. In addition, young infants have immature acetylcholine receptors which may result in greater variability in neuromuscular blockade response. Pharmacodynamics vary with age, rocuronium dose, and concomitant anesthesia. In general, infants reach maximum effect in 30 to 60 seconds after IV administration. Infants younger than 3 months may reach maximum effect more quickly (30 seconds or less) than older infants and other pediatric populations. In general, the duration of clinical effect is approximately 40 to 70 minutes; in infants younger than 3 months, the duration of action after 0.6 mg/kg IV was 60 minutes.

Children 3 to 11 years
Mean Vd of rocuronium was 0.18 to 0.21 L/kg, with a clearance of 0.35 to 0.44 L/kg/hour during clinical studies with concomitant halothane or sevoflurane induction and isoflurane/nitrous oxide maintenance anesthesia. Mean elimination half-life was 0.7 to 0.8 hours. Although a smaller Vd suggests a smaller dosage requirement, acetylcholine receptor availability must also be considered. Children have a larger number of acetylcholine receptors compared to infants, adolescents, and adults due to their larger muscle mass to fat ratio. The plasma concentration of a drug needed to maintain paralysis increases as receptor numbers increase. Therefore, dosage requirements on an mg/kg basis are higher in children than in other populations. Pharmacodynamics vary with age, rocuronium dose, and concomitant anesthesia. In general, children reach maximum effect in 30 to 60 seconds after IV administration. Duration of clinical effect is approximately 20 to 53 minutes. Clinical duration after 0.6 mg/kg IV is shortest in children 3 to 11 years of age (median 36.7 minutes).

Children and Adolescents 12 to 17 years
Under sevoflurane induction and isoflurane/nitrous oxide maintenance, adolescents demonstrated a mean Vd of 0.18 L/kg. Clearance was slower (0.29 L/kg/hour) compared to younger children, but the elimination half-life remained about the same (0.8 hours). Pharmacodynamics vary with age, rocuronium dose, and concomitant anesthesia. In general, adolescents reach maximum effect in 60 seconds after IV administration. Duration of clinical effect is approximately 40 to 70 minutes.

Hepatic Impairment
Rocuronium pharmacokinetics in pediatric patients with hepatic dysfunction have not been adequately studied. In adult patients with hepatic impairment, the clinical duration of action can be up to 1.5 times that of patients with normal hepatic function. This increase in duration is consistent with an increased Vd; Vd doubles in adult patients with hepatic dysfunction (0.53 L/kg) when compared to healthy adults (0.25 to 0.26 L/kg), making it more difficult to initially achieve adequate neuromuscular blockade with standard doses. In addition, rocuronium is primarily excreted by the liver. Plasma half-life in patients with hepatic dysfunction is approximately twice that of patients with normal hepatic function.

Renal Impairment
Rocuronium pharmacokinetics have not been adequately studied in pediatric patients with renal impairment; however, based on adult data, major clinically significant alterations are not expected. Duration of neuromuscular blockade is not prolonged in adult patients with renal dysfunction, but substantial individual variability can be seen. In general, adult patients undergoing cadaver kidney transplant may have a small reduction in clearance that is offset pharmacokinetically by a corresponding increase in Vd; the net effect is an unchanged plasma half-life.

Obesity
Rocuronium was dosed according to ABW in most clinical studies. Clinically significant differences in the onset, duration, recovery, or reversal of rocuronium-induced neuromuscular block were not noted among patients who were at least 30% or more above their ideal body weight (IBW). Further, obese patients who received 0.6 mg/kg IV according to IBW had a longer time to maximum block, a shorter median clinical duration of 25 (range, 14 to 29) minutes, and did not achieve intubating conditions as compared with patients who received 0.6 mg/kg according to ABW. In contrast, some studies suggest dosing based on IBW is associated with a similar onset of paralysis and intubating conditions, with a shorter duration of effect. In a study of 12 adult female patients with a body mass index (BMI) more than 40 kg/m2, the duration of effect was more than double (55.5 minutes) when rocuronium 0.6 mg/kg IV was dosed based on ABW instead of IBW (22.3 minutes). In another study, 51 adult patients with a median BMI of 44 kg/m2 had a median duration of effect of 32, 38, and 42 minutes when administered rocuronium 0.6 mg/kg IV based on IBW, IBW plus 20% of excess weight (corrected body weight [CBW] 20%), or CBW40%, respectively.