PANCURONIUM 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 pancuronium with the cap and ferrule intact, in a manner that minimizes the possibility of selecting the wrong product.
Intravenous Administration
-Only experienced clinicians, familiar with the use of neuromuscular blocking drugs, should administer or supervise the use of pancuronium. Adequacy of respiration must be assured through assisted or controlled ventilation.
-To avoid distress to the patient, pancuronium should be administered only after unconsciousness has been induced. Adequate amnesia, sedation, and analgesia should accompany neuromuscular blockade.

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

Continuous IV Infusion
NOTE: Due to pancuronium's long duration of action, the use of shorter-acting agents is preferred when continuous infusion is the desired method of drug administration.
-Dilute to a concentration of 0.01 to 0.8 mg/mL in a compatible IV infusion solution (i.e., 0.9% Sodium Chloride Injection, 5% Dextrose Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, or Lactated Ringer's Injection).
-Infuse at a rate based on patient response and requirements.
-A peripheral nerve stimulator is recommended to monitor pancuronium'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: Dilution is stable for 48 hours at room temperature.

Although rare, severe anaphylactic or anaphylactoid reactions to neuromuscular blocking agents (NMBAs), including pancuronium, 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. Pancuronium has minimal histamine-release even at larger 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, erythema, rash, pruritus, urticaria, hypotension, tachycardia) related to histamine release have been reported after pancuronium 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 pancuronium is capable of triggering hyperthermia. However, because of the potentially fatal outcome, all patients undergoing anesthesia with administration of neuromuscular blockers, such as pancuronium, should be considered at risk.

Pancuronium 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 pancuronium 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.

Sinus tachycardia, hypertension, and increased cardiac output may occur secondary to the vagolytic activity of pancuronium. After rapid administration, heart rate can increase by as much as 20%. Tachycardia is blocked by prior administration of atropine. It appears to be unrelated to the dose of pancuronium administered.

Awake, paralyzed patient-anxiety and panic may be the most bothersome adverse effect associated with neuromuscular blockade. Neuromuscular blockers, such as pancuronium, 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 pancuronium 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.

Hypersalivation after pancuronium administration may occur during light anesthesia, especially if no anticholinergic premedication is given.

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

Pancuronium 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 pancuronium 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.

Pancuronium is contraindicated in patients known to have a pancuronium bromide hypersensitivity. Use pancuronium with caution in patients with neuromuscular blocking agent hypersensitivity since cross-reactivity between neuromuscular blocking agents, both depolarizing and non-depolarizing, has been reported. Severe anaphylactic reactions to neuromuscular blocking agents, including pancuronium, 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 pancuronium'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 pancuronium; carefully consider each patient's clinical condition when dosing pancuronium 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 pancuronium 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), including pancuronium, with caution in patients with asthma or other pulmonary conditions. NMBAs stimulate histamine release, which could exacerbate asthma. Although histamine release is not a characteristic action of pancuronium, reactions possibly mediated by histamine release have been reported. 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 chronic obstructive pulmonary disease (COPD) or neonatal chronic lung disease (CLD). Carefully monitor respiratory status and adequacy of ventilation after drug recovery until the patient is clearly stabilized.

Use pancuronium 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 pancuronium 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 when administering subsequent doses when it is uncertain whether maximum effect has been attained.

Use pancuronium with caution in patients with hepatic disease. Consider the possibility of slower onset, higher total dosage, and prolongation of neuromuscular blockade when pancuronium is used in patients with hepatic disease and/or biliary tract disease. The doubled elimination half-life and reduced plasma clearance determined in patients with hepatic and/or biliary tract disease, as well as limited data showing that recovery time is prolonged in patients with biliary obstruction, suggest that prolongation of neuromuscular blockade may occur. Also, these conditions are characterized by an increased volume of distribution of pancuronium, suggesting that the total initial dose to achieve adequate relaxation may, in some cases, be high.

Use pancuronium with caution in patients with renal disease or renal impairment. If pancuronium is used in a patient with renal failure, consider that the rate of recovery of neuromuscular blockade is variable and sometimes very much slower than normal.

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 pancuronium is capable of triggering hyperthermia.

Use pancuronium with caution in patients with preexisting tachycardia or those who cannot tolerate an increase in heart rate. Pancuronium can cause tachycardia as a result of vagolytic action and increased norepinephrine release.

Neonates are especially sensitive to nondepolarizing neuromuscular blocking agents, such as pancuronium. A test dose is recommended to be given in neonates to measure responsiveness. The prolonged use of pancuronium for the management of neonates undergoing mechanical ventilation has been associated in rare cases with severe skeletal muscle weakness that may first be noted during attempts to wean the neonate from the ventilator; these patients usually receive other drugs, such as antibiotics, which may enhance neuromuscular blockade. Microscopic changes consistent with disuse atrophy have been noted at autopsy. Although a cause-and-effect relationship has not been established, consider the benefits-to-risk ratio when there is a need for neuromuscular blockade to facilitate long-term mechanical ventilation of neonates. Also, pancuronium products contain benzyl alcohol as a preservative. The recommended dosage range of pancuronium for preterm and term infants includes amounts of benzyl alcohol well below that associated with toxicity; however, the minimum amount of benzyl alcohol at which toxicity may occur is unknown. If the patient requires more than the recommended dosages or other medications containing this preservative, consider the daily metabolic load of benzyl alcohol from these combined sources. Excessive amounts of benzyl alcohol in neonates have been associated with hypotension, metabolic acidosis, and kernicterus. A "gasping syndrome" characterized by CNS depression, metabolic acidosis, and gasping respirations has been associated with benzyl alcohol dosages more than 99 mg/kg/day in neonates. Premature neonates and low-birth-weight neonates may be more likely to develop toxicity.

Description: Pancuronium is a parenteral, long-acting, nondepolarizing, neuromuscular blocking agent indicated as an adjunct to general anesthesia to facilitate tracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation. Pancuronium is approximately one-third less potent than vecuronium, with a longer duration of action at initially equipotent doses. Pancuronium has little effect on histamine release at usual doses and is not likely to cause clinically significant bronchospasm compared to agents with histamine-releasing properties such as atracurium and succinylcholine; however, pancuronium may cause significant tachycardia and hypertension due to vagolytic properties. It is one of the most common neuromuscular blockers used in critically ill children. Due to its long duration of action, intermittent pancuronium doses may be considered as an alternative to continuous infusions of shorter-acting neuromuscular blocking agents for certain patients requiring sustained neuromuscular blockade. Pancuronium is FDA-approved for use in pediatric patients with no defined age range and has been used in 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.
-Guidelines for sustained neuromuscular blockade in critically ill children recommend calculating the dose according to ideal body weight (IBW).
-Use a peripheral nerve stimulator during continuous infusion or repeated dosing to monitor pancuronium'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 pancuronium and still require paralysis to another agent.

For muscular relaxation during non-emergent endotracheal intubation and rapid-sequence intubation (RSI)*:
Intravenous dosage:
Neonates: 0.05 to 0.1 mg/kg/dose IV. Consider a test dose of 0.02 mg/kg to measure responsiveness. Onset of intubating conditions is 1 to 3 minutes. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Infants, Children, and Adolescents: 0.06 to 0.1 mg/kg/dose IV. Usual dose: 0.1 mg/kg/dose. Onset of intubating conditions is 2 to 5 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: 0.05 to 0.1 mg/kg/dose IV every 4 to 6 hours as needed; adjust dose and interval to patient's twitch response. Consider a test dose of 0.02 mg/kg to measure responsiveness. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Infants: 0.05 to 0.1 mg/kg/dose IV every 4 to 6 hours as needed; adjust dose and interval to patient's twitch response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents: 0.05 to 0.15 mg/kg/dose IV every 4 to 6 hours as needed; adjust dose and interval to patient's twitch response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Continuous Intravenous Infusion dosage:
Infants: 0.1 mg/kg IV bolus, followed by 0.4 to 0.6 mcg/kg/minute continuous IV infusion; titrate to patient's twitch response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents: 0.15 mg/kg IV bolus, followed by 0.5 to 1 mcg/kg/minute continuous IV infusion; titrate to patient's twitch response. 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: 0.04 to 0.1 mg/kg/dose IV as needed; adjust dose and interval to patient's twitch response. Consider a test dose of 0.02 mg/kg to measure responsiveness. Later incremental doses starting at 0.01 mg/kg may be used. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Infants, Children, and Adolescents: 0.04 to 0.1 mg/kg/dose IV as needed; adjust dose and interval to patient's twitch response. Later incremental doses starting at 0.01 mg/kg may be used. 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 hepatic impairment are not available. Consider the possibility of slower onset, higher total dosage, and prolongation of neuromuscular blockade when pancuronium is used in patients with hepatic disease and/or biliary tract disease.

Patients with Renal Impairment Dosing
If pancuronium is used in a patient with renal failure, consider that the rate of recovery of neuromuscular blockade is variable and sometimes very much slower than normal.
CrCl more than 50 mL/minute/1.73 m2: No initial dosage adjustment required; monitor carefully and adjust dosage to clinical effect.
CrCl 10 to 50 mL/minute/1.73 m2: Administer 50% of normal dosage; monitor carefully and adjust dosage to clinical effect.
CrCl less than 10 mL/minute/1.73 m2: Avoid use.

*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 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 neuromusclar blocking agents (NMBAs) such as pancuronium 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.

Pancuronium is a bisquaternary aminosteroid. In addition to its therapeutic actions, pancuronium can cause an increase in heart rate and blood pressure due to vagolytic and weak sympathomimetic properties. Pancuronium produces little histamine release and no ganglion blockade, so hypotension and bronchospasm are not associated with its use.

Pharmacokinetics: Pancuronium is administered intravenously. Protein binding is approximately 87%, primarily to gamma globulin and albumin. After administration, pancuronium distributes to the extracellular space. Vd ranges from 0.24 to 0.28 L/kg in adult patients, which is similar to that of children (0.2 L/kg). Plasma clearance is approximately 1.1 to 1.9 mL/kg/minute in both pediatric and adult patients. Metabolism occurs via hepatic pathways to at least 3 metabolites. Up to 25% of an administered pancuronium dose is recovered as the 3-hydroxy metabolite, which is approximately half as potent as the parent drug. Less than 5% of the administered dose is recovered as the 17-hydroxy and 3, 17-hydroxy metabolites, both of which are 50 times less potent than pancuronium. Of a pancuronium dose, 40% is excreted in the urine and 11% in the bile. Elimination half-life ranges from 89 to 161 minutes. In general, the pharmacokinetic parameters of pancuronium in children are comparable to those in adults.

Affected cytochrome P450 isoenzymes and drug transporters: none


-Route-Specific Pharmacokinetics
Intravenous Route
In general, neuromuscular blockade begins within 2 to 5 minutes and lasts 24 minutes in pediatric patients compared to the onset of 3 to 5 minutes and duration of 22 minutes in adults. Intensity and duration of action are affected by the dose, age of the patient, and the use of concurrent anesthetics and other neuromuscular blocking agents.


-Special Populations
Pediatrics
Neonates and Infants
Neonates and infants have less muscle mass, and therefore fewer acetylcholine receptors, compared to older pediatric populations; this results in the need for lower plasma concentrations of pancuronium to maintain paralysis. Additionally, hepatic enzyme immaturity may play a role in the lower dosage requirement. The dose required to produce 95% suppression of the muscle twitch response (ED95) of pancuronium in infants is 50 to 66 mcg/kg, which is less than children (93 mcg/kg) but comparable to adults (50 to 67 mcg/kg). Onset of action after a dose of 0.15 mg/kg in neonates is 1.5 to 2 minutes. Onset of action in infants is 2 to 5 minutes.

Children
Vd of pancuronium in children is 0.2 L/kg, compared to 0.24 to 0.28 L/kg in adults. 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 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 mg/kg basis are higher in children than in infants and adults. The dose required to produce 95% suppression of the muscle twitch response (ED95) of pancuronium is significantly greater in children (93 mcg/kg) than in infants (50 to 66 mcg/kg) and adults (50 to 67 mcg/kg). In a pharmacokinetic study of children ages 3 to 6 years (n = 12), those receiving pancuronium 0.1 mg/kg demonstrated a clearance of 1.7 +/- 0.2 mL/kg/minute and an elimination half-life of 103 +/- 23 minutes. These values are consistent with adult parameters. Onset of action is 2 to 4 minutes, and duration of clinical effect is approximately 24 minutes in children.

Hepatic Impairment
Vd is increased by approximately 50%, plasma clearance is reduced by 22%, and elimination half-life is doubled in patients with hepatic cirrhosis. In patients with biliary obstruction, similar changes are seen in Vd and elimination half-life; plasma clearance is reduced by at least 50%.

Renal Impairment
Vd of pancuronium is often variable and may be increased in patients with renal failure. Plasma clearance is reduced by approximately 60% and elimination half-life is doubled. Rate of recovery is variable and may be prolonged.