Pharmacokinetics

At clinical doses of 0.04 to 0.1 mg/kg, 60 to 80% of vecuronium bromide is usually bound to plasma protein. The distribution half-life following a single intravenous dose (range 0.025 to 0.28 mg/kg) is approximately 4 minutes. Elimination half-life over this sample dosage range is approximately 65 to 75 minutes in healthy surgical patients and in renal failure patients undergoing transplant surgery.

In late pregnancy, elimination half-life may be shortened to approximately 35 to 40 minutes. The volume of distribution at steady state is approximately 300 to 400 mL/kg; systemic rate of clearance is approximately 3 to 4.5 mL/kg/minute. In man, urine recovery of vecuronium varies from 3 to 35% within 24 hours. Data derived from patients requiring insertion of a T-tube in the common bile duct suggests that 25 to 50% of a total intravenous dose of vecuronium may be excreted in bile within 42 hours. Only unchanged vecuronium has been detected in human plasma following use during surgery. In addition, one metabolite 3-desacetyl vecuronium has been rarely detected in human plasma following prolonged clinical use in the ICU (see PRECAUTIONS-Long-Term Use in ICU). The 3-desacetyl vecuronium metabolite has been recovered in the urine of some patients in quantities that account for up to 10% of injected dose; 3-desacetyl vecuronium has also been recovered by T-tube in some patients, accounting for up to 25% of the injected dose.

This metabolite has been judged by animal screening (dogs and cats) to have 50% or more of the potency of vecuronium; equipotent doses are of approximately the same duration as vecuronium in dogs and cats. Biliary excretion accounts for about half the dose of vecuronium within 7 hours in the anesthetized rat. Circulatory bypass of the liver (cat preparation) prolongs recovery from vecuronium. Limited data derived from patients with cirrhosis or cholestasis suggests that some measurements of recovery may be doubled in such patients. In patients with renal failure, measurements of recovery do not differ significantly from similar measurements in healthy patients.

Studies involving routine hemodynamic monitoring in good risk surgical patients reveal that the administration of vecuronium, in doses up to three times that needed to produce clinical relaxation (0.15 mg/kg), did not produce clinically significant changes in systolic, diastolic, or mean arterial pressure. The heart rate, under similar monitoring, remained unchanged in some studies and was lowered by a mean of up to 8% in other studies. A large dose of 0.28 mg/kg administered during a period of no stimulation, while patients were being prepared for coronary artery bypass grafting, was not associated with alterations in rate-pressure-product or pulmonary capillary wedge pressure. Systemic vascular resistance was lowered slightly and cardiac output was increased insignificantly. (The drug has not been studied in patients with hemodynamic dysfunction secondary to cardiac valvular disease.) Limited clinical experience with use of vecuronium bromide during the surgery for pheochromocytoma has shown that administration of this drug is not associated with changes in blood pressure or heart rate.

Unlike other nondepolarizing skeletal muscle relaxants, vecuronium has no clinically significant effects on hemodynamic parameters. Vecuronium will not counteract those hemodynamic changes or known side effects produced by or associated with anesthetic agents, other drugs, or various other factors known to alter hemodynamics.

Anaphylaxis

Severe anaphylactic reactions to neuromuscular blocking agents, including vecuronium bromide, have been reported. These reactions have in some cases 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 individuals who have had previous anaphylactic reactions to other neuromuscular blocking agents since cross-reactivity between neuromuscular blocking agents, both depolarizing and non-depolarizing, has been reported in this class of drugs.

Risk of Death due to Medication Errors

Administration of vecuronium bromide for injection results in paralysis, which may lead to respiratory arrest and death; this progression 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 communicated.

Renal Failure

Vecuronium is well tolerated without clinically significant prolongation of neuromuscular blocking effect in patients with renal failure who have been optimally prepared for surgery by dialysis. Under emergency conditions in anephric patients, some prolongation of neuromuscular blockade may occur; therefore, if anephric patients cannot be prepared for non-elective surgery, a lower initial dose of vecuronium should be considered.

Altered Circulation Time

Conditions associated with slower circulation time in cardiovascular disease, old age, edematous states resulting in increased volume of distribution may contribute to delay in onset time; therefore, dosage should not be increased.

Hepatic Disease

Experience in patients with cirrhosis or cholestasis has revealed prolonged recovery time in keeping with the role the liver plays in vecuronium metabolism and excretion (see CLINICAL PHARMACOLOGY- Pharmacokinetics). Data currently available do not permit dosage recommendations in patients with impaired liver function.

Long-Term Use in ICU

In the intensive care unit, long-term use of neuromuscular blocking drugs to facilitate mechanical ventilation may be associated with prolonged paralysis and/or skeletal muscle weakness, that may be first noted during attempts to wean such patients from the ventilator. Typically, such patients receive other drugs such as broad spectrum antibiotics, narcotics and/or steroids and may have electrolyte imbalance and diseases which lead to electrolyte imbalance, hypoxic episodes of varying duration, acid-base imbalance and extreme debilitation, any of which may enhance the actions of a neuromuscular blocking agent. Additionally, patients immobilized for extended periods frequently develop symptoms consistent with disuse muscle atrophy. The recovery picture may vary from regaining movement and strength in all muscles to initial recovery of movement of the facial and small muscles of the extremities then to the remaining muscles. In rare cases recovery may be over an extended period of time and may even, on occasion, involve rehabilitation. Therefore, when there is a need for long term mechanical ventilation, the benefits-to-risk ratio of neuromuscular blockade must be considered.

Continuous infusion or intermittent bolus dosing to support mechanical ventilation has not been studied sufficiently to support dosage recommendations. IN THE INTENSIVE CARE UNIT, APPROPRIATE MONITORING, WITH THE USE OF A PERIPHERAL NERVE STIMULATOR TO ASSESS THE DEGREE OF NEUROMUSCULAR BLOCKADE IS RECOMMENDED TO HELP PRECLUDE POSSIBLE PROLONGATION OF THE BLOCKADE. WHENEVER THE USE OF VECURONIUM OR ANY NEUROMUSCULAR BLOCKING AGENT IS CONTEMPLATED IN THE ICU, IT IS RECOMMENDED THAT NEUROMUSCULAR TRANSMISSION BE MONITORED CONTINUOUSLY DURING ADMINISTRATION AND RECOVERY WITH THE HELP OF A NERVE STIMULATOR. ADDITIONAL DOSES OF VECURONIUM OR ANY OTHER NEUROMUSCULAR BLOCKING AGENT SHOULD NOT BE GIVEN BEFORE THERE IS A DEFINITE RESPONSE TO T1 OR TO THE FIRST TWITCH. IF NO RESPONSE IS ELICITED, INFUSION ADMINISTRATION SHOULD BE DISCONTINUED UNTIL A RESPONSE RETURNS.

Severe Obesity or Neuromuscular Disease

Patients with severe obesity or neuromuscular disease may pose airway and/or ventilatory problems requiring special care before, during and after the use of neuromuscular blocking agents such as vecuronium.

Malignant Hyperthermia

Many drugs used in anesthetic practice are suspected of being capable of triggering a potentially fatal hypermetabolism of skeletal muscle known as malignant hyperthermia. There are insufficient data derived from screening in susceptible animals (swine) to establish whether or not vecuronium is capable of triggering hyperthermia.

CNS

Vecuronium has no known effect on consciousness, the pain threshold or cerebration. Administration must be accompanied by adequate anesthesia or sedation.

Drug Interactions

Prior administration of succinylcholine may enhance the neuromuscular blocking effect of vecuronium and its duration of action. If succinylcholine is used before vecuronium, the administration of vecuronium should be delayed until the succinylcholine effect shows signs of wearing off. With succinylcholine as the intubating agent, initial doses of 0.04 to 0.06 mg/kg of vecuronium may be administered to produce complete neuromuscular block with clinical duration of action of 25 to 30 minutes (see CLINICAL PHARMACOLOGY).

The use of vecuronium before succinylcholine, in order to attenuate some of the side effects of succinylcholine, has not been sufficiently studied.

Other nondepolarizing neuromuscular blocking agents (pancuronium, d-tubocurarine, metocurine, and gallamine) act in the same fashion as does vecuronium; therefore, these drugs and vecuronium, may manifest an additive effect when used together. There are insufficient data to support concomitant use of vecuronium and other competitive muscle relaxants in the same patient.

Drug/Laboratory Test Interactions

None known.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic or mutagenic potential or impairment of fertility.

Pregnancy

Labor and Delivery

The use of vecuronium in patients undergoing cesarean section has been reported in the literature. Following tracheal intubation with succinylcholine, vecuronium dosages of 0.04 mg/kg (n=11) and 0.06 to 0.08 mg/kg (n=20) were administered. The umbilical venous plasma concentrations were 11% of maternal concentrations at delivery and mean neonate APGAR scores at 5 minutes were ≥ 9 in both reports. The action of neuromuscular blocking agents may be enhanced by magnesium salts administered for the management of toxemia of pregnancy.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when vecuronium is administered to a nursing woman.

Pediatric Use

Infants under 1 year of age but older than 7 weeks, also tested under halothane anesthesia, are moderately more sensitive to vecuronium on a mg/kg basis than adults and take about 1.5 times as long to recover. See DOSAGE AND ADMINISTRATION-Use in Pediatrics subsection for recommendations for use in pediatric patients 7 weeks to 16 years of age. The safety and effectiveness of vecuronium in pediatric patients less than 7 weeks of age have not been established.

Geriatric Use

Clinical studies of vecuronium did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. There are some reports in the peer reviewed literature of increased effect and longer duration of action of vecuronium in the elderly compared to younger patients. However, other reports have found no significant differences between healthy elderly and younger adults. Advanced age or other conditions associated with slower circulation time, may be associated with a delay in onset time (see PRECAUTIONS– Altered Circulation Time). Nevertheless, recommended doses of vecuronium should not be increased in these patients to reduce onset time, as higher doses produce a longer duration of action (see CLINICAL PHARMACOLOGY). Dose selections for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Close monitoring of neuromuscular function is recommended.

Use by Continuous Infusion

After an intubating dose of 0.08 to 0.1 mg/kg, a continuous infusion of 1 mcg/kg/min can be initiated approximately 20 to 40 min later. Infusion of vecuronium bromide should be initiated only after early evidence of spontaneous recovery from the bolus dose. Long-term intravenous infusion to support mechanical ventilation in the intensive care unit has not been studied sufficiently to support dosage recommendations. (See PRECAUTIONS-Long-Term Use in ICU.)

The infusion of vecuronium bromide should be individualized for each patient. The rate of administration should be adjusted according to the patient's twitch response as determined by peripheral nerve stimulation. An initial rate of 1 mcg/kg/min is recommended, with the rate of the infusion adjusted thereafter to maintain a 90% suppression of twitch response. Average infusion rates may range from 0.8 to 1.2 mcg/kg/min.

Inhalation anesthetics, particularly enflurane and isoflurane may enhance the neuromuscular blocking action of nondepolarizing muscle relaxants. In the presence of steady state concentrations of enflurane or isoflurane, it may be necessary to reduce the rate of infusion 25 to 60%, 45 to 60 minutes after the intubating dose. Under halothane anesthesia it may not be necessary to reduce the rate of infusion.

Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of vecuronium bromide infusion may be expected to proceed at rates comparable to that following a single bolus dose (see CLINICAL PHARMACOLOGY).

Infusion solutions of vecuronium bromide can be prepared by adding vecuronium bromide with an appropriate infusion solution such as Dextrose 5% Injection, Sodium Chloride 0.9% Injection, Dextrose 5% and Sodium Chloride 0.9% Injection, or Lactated Ringer's Injection.

Unused portions of infusion solutions should be discarded.

Infusion rates of vecuronium bromide can be individualized for each patient using the following table:

The following table is a guideline for mL/min delivery for a solution of 0.1 mg/mL (10 mg in 100 mL) with an infusion pump.

NOTE: If a concentration of 0.2 mg/mL is used (20 mg in 100 mL), the rate should be decreased by one-half.

Use in Pediatrics

Pediatric patients (10 to 16 years of age) have approximately the same dosage requirements (mg/kg) as adults and may be managed the same way. Younger pediatric patients (1 to 10 years of age) may require a slightly higher initial dose and may also require supplementation slightly more often than adults.

Infants under 1 year of age but older than 7 weeks are moderately more sensitive to vecuronium bromide on a mg/kg basis than adults and take about 1½ times as long to recover. (See PRECAUTIONS - Pediatric Use.) Information presently available does not permit recommendation on usage in pediatric patients less than 7 weeks of age (see PRECAUTIONS-Pediatric Use). There are insufficient data concerning continuous infusion of vecuronium in pediatric patients, therefore, no dosing recommendations can be made.

COMPATIBILITY

Vecuronium bromide is compatible in solution with:

• Sodium Chloride 0.9% Injection
• Dextrose 5% Injection
• Sterile Water for Injection
• Dextrose 5% in Sodium Chloride 0.9% Injection
• Lactated Ringer's Injection

Use within 24 hours of mixing with the above solutions.

Vecuronium bromide is also compatible in solution with: bacteriostatic water for injection (NOT FOR USE IN NEWBORNS)

Use within 5 days of mixing with the above solution.

Reconstituted vecuronium bromide, which has an acid pH, should not be mixed with alkaline solutions (e.g., barbiturate solutions such as thiopental) in the same syringe or administered simultaneously during intravenous infusion through the same needle or through the same intravenous line.

After Reconstitution

See DOSAGE AND ADMINISTRATION – Compatibility for diluents compatible with Vecuronium Bromide for Injection.

• When reconstituted with bacteriostatic water for injection: CONTAINS BENZYL ALCOHOL, WHICH IS NOT INTENDED FOR USE IN NEWBORNS. Use within 5 days. May be stored at room temperature or refrigerated.
• When reconstituted with sterile water for injection or other compatible intravenous solutions: Refrigerate vial. Use within 24 hours. Single use only. Discard unused portion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Risk of Medication Errors:  Accidental administration of neuromuscular blocking agents may be fatal. Store vecuronium bromide with the cap and ferrule intact and in a manner that minimizes the possibility of selecting the wrong product.

STORAGE

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light. Retain in carton until time of use.

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

Rev. E 7/2018