Norcuron (Vecuronium)

NORCURON®

Organon

Vecuronium Bromide

Nondepolarizing Neuromuscular Blocking Agent

Action And Clinical Pharmacology: Vecuronium is a nondepolarizing neuromuscular blocking agent possessing all of the characteristic curariform pharmacological actions of this class of drugs. It acts by competing for cholinergic receptors at the motor end-plate. The antagonism to acetylcholine is inhibited and neuromuscular block is reversed by acetylcholinesterase inhibitors such as neostigmine, edrophonium, and pyridostigmine. Vecuronium is about a third more potent than pancuronium; the duration of neuromuscular blockade produced by vecuronium is shorter than that of pancuronium at initially equipotent doses. The time to onset of paralysis decreases and the duration of maximum effect increases with increasing vecuronium doses. The use of a peripheral nerve stimulator is of benefit in assessing the degree of muscular relaxation.

The ED90 (dose required to produce 90% suppression of the muscle twitch response while under balanced anesthesia) has averaged 0.057 mg/kg (0.049 to 0.062 mg/kg in various studies). An initial vecuronium dose of 0.08 to 0.10 mg/kg generally produces first depression of twitch in approximately 1 minute, good or excellent intubation conditions within 2.5 to 3.0 minutes, and maximum neuromuscular blockade within 3 to 5 minutes of injection in most patients. Under balanced anesthesia, the time to 25% recovery of the control twitch response (clinical duration) is approximately 25 to 40 minutes after injection and recovery is usually 95% complete approximately 45 to 65 minutes after injection of an intubating dose.

The neuromuscular blocking action of vecuronium is slightly enhanced in the presence of potent inhalation anesthetics. If vecuronium is first administered more than 5 minutes after the start of the inhalation of enflurane, isoflurane, or halothane, or when steady state has been achieved, the intubating dose of vecuronium may be decreased by approximately 15% (see Dosage).

Prior administration of succinylcholine may enhance the neuromuscular blocking effect of vecuronium and its duration of action. With succinylcholine as the intubating agent, initial doses of 0.04 to 0.06 mg/kg of vecuronium will produce complete neuromuscular block with clinical duration of action of 25 to 30 minutes. If succinylcholine is used prior to vecuronium, the administration of vecuronium should be delayed until the patient starts recovering from succinylcholine-induced neuromuscular blockade. The effect of prior use of other nondepolarizing neuromuscular blocking agents on the activity of vecuronium has not been studied (see Precautions, Drug Interactions).

Repeated administration of maintenance doses of vecuronium has little or no cumulative effect on the duration of neuromuscular blockade. Therefore, repeat doses can be administered at relatively regular intervals with predictable results. After an initial dose of 0.08 to 0.10 mg/kg under balanced anesthesia, the first maintenance dose of 0.010 to 0.015 mg/kg is generally required within 25 to 40 minutes; subsequent maintenance doses, if required, may be administered at approximately 12 to 15 minute intervals. Halothane anesthesia increases the clinical duration of the maintenance dose only slightly. Under enflurane, a maintenance dose of 0.010 mg/kg is approximately equal to a 0.015 mg/kg dose under balanced anesthesia.

The recovery index (time from 25% to 75% recovery) is approximately 15 to 25 minutes under balanced or halothane anesthesia. When recovery from vecuronium neuromuscular blocking effect begins, it proceeds more rapidly than recovery from pancuronium. Once spontaneous recovery has started, the neuromuscular block produced by vecuronium is readily reversed with various anticholinesterase agents, e.g., pyridostigmine, neostigmine, or edrophonium in conjunction with an anticholinergic agent such as atropine or glycopyrrolate. There have been no reports of recurarization following satisfactory reversal of vecuronium induced neuromuscular blockade; rapid recovery is a finding consistent with its short elimination half-life.

Pharmacokinetics: At clinical doses of 0.04 to 0.10 mg/kg, 60 to 80% of vecuronium is usually bound to plasma protein. The distribution half-life following a single i.v. dose (range 0.025 to 0.280 mg/kg) is approximately 4 minutes. Elimination half-life over this same 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/minute/kg. In man, urinary 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 suggest that 25 to 50% of a total i.v. dose of vecuronium may be excreted in bile within 42 hours. Only unchanged vecuronium has been detected in human plasma following clinical use. One metabolite, 3-deacetyl vecuronium, has been recovered in the urine of some patients in quantities that account for up to 10% of the injected dose; 3-deacetyl 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 the potency of vecuronium, equipotent doses are of approximately the same duration as vecuronium in dogs and cats.

Limited data derived from the patients with cirrhosis or cholestasis and in the elderly, suggest 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 3 times that needed to produce clinical relaxation (0.15 mg/kg) did not produce clinically significant changes in systolic, diastolic or mean arterial blood pressure. The heart rate 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 ouput was increased insignificantly. (The drug has not been studied in patients with hemodynamic dysfunction secondary to cardiac valvular disease).

Limited clinical experience in 3 patients with pheochromocytoma has shown that administration of this drug during surgery 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 and will not counteract those hemodynamic changes or known side effects produced by or associated with anesthetic agents.

In one clinical study, the duration of action of vecuronium was increased 5-fold during hypothermic cardiopulmonary bypass.

Preliminary data on histamine assay in 16 patients and available clinical experience in more than 600 patients indicate that hypersensitivity reactions such as bronchospasm, flushing, redness, hypotension, tachycardia, and other reactions commonly associated with histamine release are unlikely to occur.

Indications And Clinical Uses: As an adjunct to general anesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.

Contra-Indications: Hypersensitivity to the drug. Pregnant and lactating women, since reproductive studies in animals have not yet been performed (see Warnings).

Manufacturers’ Warnings In Clinical States: General: Vecuronium should be administered in carefully adjusted dosage by or under the supervision of experienced clinicians who are familiar with its actions and the possible complications that might occur following its use. The drug should not be administered unless facilities for intubation, artificial respiration, oxygen therapy, and reversal agents are immediately available. The clinician must be prepared to assist or control respiration. A peripheral nerve stimulator should be employed to monitor drug response, need for additional relaxant, and adequacy of spontaneous recovery or anticholinesterase antagonism.

Intensive Care Unit: To reduce the possibility of prolonged neuromuscular blockade and other complications that might occur following long-term use in the ICU, vecuronium or any other neuromuscular blocking agent should be administered in carefully adjusted doses by or under the supervision of experienced clinicians who are familiar with its actions and with appropriate peripheral nerve stimulator muscle monitoring techniques.

Neuromuscular Disease: In patients who are known to have myasthenia gravis or the myasthenic (Eaton-Lambert) syndrome, small doses of vecuronium may have profound effects. In such patients, a peripheral nerve stimulator and use of a small test dose may be of particular value in assessing and monitoring dosage requirements.

Precautions: General: Limited data on histamine assay and available clinical experience indicate that hypersensitivity reactions such as bronchospasm, flushing, redness, hypotension, tachycardia and other reactions commonly associated with histamine release are unlikely to occur.

Cardiovascular: As vecuronium has no significant effects on heart rate in the recommended dosage range, it will not counteract the bradycardia produced by many anesthetic agents or vagal stimulation.

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.

Hepatic Disease: Limited 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 Pharmacology, Pharmacokinetics). Data currently available do not permit dosage recommendations in patients with impaired liver function.

Increased Volume of Distribution: The onset of action of neuromuscular blocking agents may be delayed in patients who have increased volumes of distribution as a result of old age, edematous states, or cardiovascular disease. More time should be permitted for the drug to achieve its maximal effect in these patients. Dosage should not be increased.

Long-term Use in ICU: Limited information if available concerning the efficacy and safety of long-term (days to weeks) i.v. vecuronium infusion to facilitate mechanical ventilation in the intensive care unit. In rare cases, long-term use of neuromuscular blocking drugs to facilitate mechanical ventilation in ICU settings may be associated with prolonged paralysis and/or skeletal muscle weakness, that may be first noted during attempts to wean patients from ventilator. Typically, such patients have received other drugs such as broad spectrum antibiotics, narcotics and/or steroids and may have electrolyte imbalances and diseases which lead to electrolyte imbalances, 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.

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 malignant hyperthermia.

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

Hypothermia: Hypothermia (25 to 28°C) has been associated with a decreased requirement for nondepolarizing neuromuscular blocking agents.

Burns: Resistance to nondepolarizing neuromuscular blocking agents may develop in patients with burns, depending upon the time elapsed since the injury and the size of the burn.

Pregnancy and Lactation: Animal studies have not been conducted with vecuronium. It is not known whether vecuronium can cause fetal harm when administered to a pregnant woman, or if it can affect reproductive capacity. It is not known whether vecuronium is secreted in breast milk and therefore is not recommended in lactating women.

Obstetrics: It is not known whether muscle relaxants administered during vaginal delivery have immediate or delayed adverse effects on the fetus, or increase the likelihood that resuscitation of the newborn will be necessary. The possibility that a forceps delivery will be necessary may increase.

The possibility of respiratory depression in the newborn infant should always be considered following cesarean section during which a neuromuscular blocking agent has been administered.

Children: 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 1/2 times as long to recover. Information presently available does not permit recommendations for usage of vecuronium in neonates.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have not been performed to evaluate carcinogenic or mutagenic potential or impairment of fertility.

Drug Interactions: Succinylcholine: 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 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.

Inhalation Anesthetics: Use of volatile inhalational anesthetics such as enflurane, isoflurane, and halothane with vecuronium will enhance neuromuscular blockade. Potentiation is most prominent with the use of enflurane and isoflurane.

With the above agents the initial doses of vecuronium may be the same as with balanced anesthesia unless the inhalational anesthetic has been administered for a sufficient time at a sufficient dose to have reached clinical equilibrium (see Pharmacology).

Antibiotics: Parenteral/intraperitoneal administration of high doses of certain antibiotics may intensify or produce a neuromuscular block on their own. The following antibiotics have been associated with various degrees of paralysis: aminoglycosides (such as neomycin, streptomycin, kanamycin, gentamicin, and dihydrostreptomycin); tetracyclines; bacitracin; polymyxin B; colistin; and sodium colistimethate. If these or other newly introduced antibiotics are used in conjunction with vecuronium during surgery, unexpected prolongation of neuromuscular block should be considered a possibility.

Other: Experience concerning injection of quinidine during recovery from use of other muscle relaxants suggests that recurrent paralysis may occur. This possibility must also be considered for vecuronium. Vecuronium induced neuromuscular blockade has been counteracted by alkalosis and enhanced by acidosis in experimental animals (cat). Electrolyte imbalance and diseases which lead to electrolyte imbalance, such as adrenal cortical insufficiency, have been shown to alter neuromuscular blockade. Depending on the nature of the imbalance, either enhancement or inhibition may be expected. Magnesium salts, administered for the management of toxemia of pregnancy, may enhance neuromuscular blockade.

Adverse Reactions: The most frequent adverse reaction to nondepolarizing blocking agents as a class consists of an extension of the drug’s pharmacological action beyond the time period needed for surgery and anesthesia. This may vary from skeletal muscle weakness to profound and prolonged skeletal muscle paralysis resulting in respiratory insufficiency or apnea.

Inadequate reversal of the neuromuscular blockade, although not yet reported, is possible with vecuronium as with all curariform drugs. These adverse reactions are managed by manual or mechanical ventilation until recovery is judged adequate. Little or no increase in intensity of blockade or duration of action of vecuronium is noted from the use of thiobarbiturates, narcotic analgesics, nitrous oxide, or droperidol. See Overdose for discussion of other drugs used in anesthetic practice which also cause respiratory depression.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There has been no experience with vecuronium overdosage. The possibility of iatrogenic overdosage can be minimized by carefully monitoring muscle twitch response to peripheral nerve stimulation.

Excessive doses of vecuronium can be expected to produce enhanced pharmacological effects. Residual neuromuscular blockade beyond the time period needed for surgery and anesthesia may occur with vecuronium as with other neuromuscular blockers. This may be manifested by skeletal muscle weakness, decreased respiratory reserve, low tidal volume, or apnea. A peripheral nerve stimulator may be used to assess the degree of residual neuromuscular blockade and help to differentiate residual neuromuscular blockade from other causes of decreased respiratory reserve.

Respiratory depression may be due either wholly or in part to other drugs used during the conduct of general anesthesia such as narcotics, thiobarbiturates and other CNS depressants. Under such circumstances the primary treatment is maintenance of a patent airway and manual or mechanical ventilation until complete recovery of normal respiration is assured.

Pyridostigmine, neostigmine, or edrophonium, in conjunction with atropine or glycopyrrolate will usually antagonize the skeletal muscle relaxant action of vecuronium. Satisfactory reversal can be judged by adequacy of skeletal muscle tone and by adequacy of respiration. A peripheral nerve stimulator may also be used to monitor restoration of twitch height.

Failure of prompt reversal (within 30 minutes) may occur in the presence of extreme debilitation, carcinomatosis, and with concomitant use of certain broad spectrum antibiotics, or anesthetic agents and other drugs which enhance neuromuscular blockade or cause respiratory depression on their own. Under such circumstances the management is the same as that of prolonged neuromuscular blockade. Ventilation must be supported by artificial means until the patient has resumed control of his respiration. Prior to the use of reversal agents, reference should be made to the specific package insert of the reversal agent.

Dosage And Administration: Vecuronium is for i.v. use only. This drug should be administered by or under the supervision of experienced clinicians familiar with the use of neuromuscular blocking agents. Dosage must be individualized in each case.

The dosage information which follows is derived from studies based upon units of drug per unit of body weight and is intended to serve as a guide only, especially regarding enhancement of neuromuscular blockade of vecuronium by volatile anesthetics and by prior use of succinylcholine (see Precautions, Drug Interactions).

To obtain the maximum clinical benefits of vecuronium and to minimize the possibility of overdosage, the monitoring of muscle twitch response to peripheral nerve stimulation is advised.

The recommended initial dose of vecuronium is 0.08 to 0.10 mg/kg (1.4 to 1.75 times the ED90) given as an i.v. bolus injection. This dose can be expected to produce good or excellent non-emergency intubation conditions in 2.5 to 3.0 minutes after injection. Under balanced anesthesia, clinically required neuromuscular blockade lasts approximately 25 to 30 minutes, with recovery to 25% of control achieved approximately 25 to 40 minutes after injection and recovery to 95% of control achieved approximately 45 to 65 minutes after injection. In the presence of potent inhalation anesthetics, the neuromuscular blocking effect of vecuronium is enhanced. If vecuronium is first administered more than 5 minutes after the start of administration of an inhalation agent, or when steady state has been achieved, the initial vecuronium dose may be reduced by approximately 15%, to 0.060 to 0.085 mg/kg.

Prior administration of succinylcholine may enhance the neuromuscular blocking effect and duration of action of vecuronium. If intubation is performed using succinylcholine, a reduction of the initial dose of vecuronium to 0.04 to 0.06 mg/kg with inhalation anesthesia and 0.05 to 0.06 mg/kg with balanced anesthesia may be required. The administration of vecuronium should be delayed until the succinylcholine effect shows signs of wearing off.

During prolonged surgical procedures, maintenance doses of 0.010 to 0.015 mg/kg of vecuronium are recommended. After the initial vecuronium injection, the first maintenance dose will generally be required within 25 to 40 minutes. However, clinical criteria should be used to determine the need for maintenance doses. Since vecuronium lacks clinically important cumulative effects, subsequent maintenance doses, if required, may be administered at relatively regular intervals for each patient, ranging approximately from 12 to 15 minutes under balanced anesthesia, slightly longer under inhalation agents. (If less frequent administration is desired, higher maintenance doses may be administered.)

Should there be reason for the selection of larger doses in individual patients, initial doses ranging from 0.15 mg/kg up to 0.28 mg/kg have been administered during surgery under halothane anesthesia without ill effects to the cardiovascular system being noted as long as ventilation is properly maintained (see Pharmacology).

The recovery index (time from 25% to 75% recovery) is approximately 15 to 25 minutes under balanced or halothane anesthesia. When recovery from vecuronium neuromuscular blocking effect begins, it proceeds more rapidly than recovery from pancuronium. Once spontaneous recovery has started, the neuromuscular block produced by vecuronium is readily reversed with various anticholinesterase agents, e.g., pyridostigmine, neostigmine, or edrophonium in conjunction with an anticholinergic agent such as atropine or glycopyrrolate.

Use by Infusion: Following the administration of a recommended initial bolus dose of vecuronium, a diluted solution of vecuronium can be administered by continuous infusion to adults for maintenance of neuromuscular blockade during extended surgical procedures. Long-term i.v. infusion to support mechanical ventilation in the intensive care unit has not been studied sufficiently to support dosage recommendations (see Precautions).

Infusion of vecuronium should be individualized for each patient. The rate of administration should be adjusted according to the patient’s response as determined by peripheral nerve stimulation.

Infusion of vecuronium should be initiated only after early evidence of spontaneous recovery from the bolus dose (typically 10 to 20% recovery of the initial twitch response). During balanced anesthesia, an initial infusion rate of 1 g/kg/min is recommended with subsequent rate adjustments to maintain a 90% suppression of the twitch response.

Individual infusion rates may range from 0.6 to 1.8 g/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 use infusion rates which are 25 to 60% lower than those recommended during balanced anesthesia. Reduced infusion rates may not be required during halothane anesthesia.

Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of vecuronium infusion may be expected to proceed at rates comparable to those following single bolus doses (see Pharmacology).

Infusion solutions of vecuronium can be prepared by mixing vecuronium with an appropriate infusion solution such as 5% dextrose injection, USP; 0.9% sodium chloride injection, USP; 5% dextrose and 0.9% sodium chloride injection, USP; or lactated Ringer’s injection, USP. Use within 24 hours of mixing with the above solutions. Unused portions of infusion solutions should be discarded.

Children: Older children (10 to 17 years of age) have approximately the same dosage requirements (mg/kg) as adults and may be managed the same way. Younger children (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 on a mg/kg basis than adults and take about 1 1/2 times as long to recover. See also subsection of Precautions titled Children. Information presently available does not permit recommendation on usage in neonates (see Precautions).

Reconstitution: Reconstitute each vial with 10 mL of bacteriostatic water for injection or 10 mL of compatible diluent to obtain a solution containing 1 mg/mL vecuronium bromide. Compatible diluents include: 0.9% sodium chloride injection, USP, 5% dextrose injection, USP, 5% dextrose and 0.9% sodium chloride injection, USP, sterile water for injection, USP and lactated Ringer’s injection, USP. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

When reconstituted with bacteriostatic water for injection, use within 5 days. When reconstituted with recommended diluents, use within 24 hours. Single dose vial. Discard unused portion.

Availability And Storage: Sterile freeze-dried buffered cake of very fine microscopic crystalline particles for i.v. injection only. Nonmedicinal ingredients: citric acid, mannitol, phosphoric acid, sodium hydroxide and sodium phosphate dibasic. Vials of 10 mL. Boxes of 10. Protect from light. Store at 15 to 30°C.

NORCURON® Organon Vecuronium Bromide Nondepolarizing Neuromuscular Blocking Agent

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