VECURONIUM BROMIDE- vecuronium bromide injection, powder, lyophilized, for solution
Watson Laboratories, Inc.
|THIS DRUG SHOULD BE ADMINISTERED BY ADEQUATELY TRAINED INDIVIDUALS FAMILIAR WITH ITS ACTIONS, CHARACTERISTICS, AND HAZARDS.|
Vecuronium bromide for injection is a nondepolarizing neuromuscular blocking agent of intermediate duration, chemically designated as piperidinium, 1-[(2β, 3α, 5α, 16β, 17β)-3, 17-bis (acetyloxy)-2-(1-piperidinyl) androstan-16-yl]-1-methyl-, bromide. The structural formula is:
Its molecular formula is C34 H57 BrN2 O4 with molecular weight 637.74.
Vecuronium bromide for injection is supplied as a sterile nonpyrogenic freeze-dried buffered cake of very fine microscopic crystalline particles for intravenous injection only. Each 10 mL vial contains 10 mg vecuronium bromide, 20.75 mg citric acid anhydrous, 16.25 mg sodium phosphate dibasic anhydrous, 97 mg mannitol (to adjust tonicity), sodium hydroxide and/or phosphoric acid to buffer and adjust to a pH of 4. Each 20 mL vial contains 20 mg of vecuronium bromide, 41.5 mg citric acid anhydrous, 32.5 mg sodium phosphate dibasic anhydrous, 194 mg mannitol (to adjust tonicity), sodium hydroxide and/or phosphoric acid to buffer and adjust to a pH of 4.
Vecuronium bromide is a nondepolarizing neuromuscular blocking agent possessing all of the characteristic pharmacological actions of this class of drugs (curariform). 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 1/3 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 recommended in assessing the degree of muscular relaxation with all neuromuscular blocking drugs. The ED90 (dose required to produce 90% suppression of the muscle twitch response with balanced anesthesia) has averaged 0.057 mg/kg (0.049 to 0.062 mg/kg in various studies). An initial vecuronium bromide 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 minutes, and maximum neuromuscular blockade within 3 to 5 minutes of injection in most patients.
Under balanced anesthesia, the time to recovery to 25% of control (clinical duration) is approximately 25 to 40 minutes after injection and recovery is usually 95% complete approximately 45-65 minutes after injection of 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 AND ADMINISTRATION section). 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 0.04-0.06 mg/kg of vecuronium bromide will produce complete neuromuscular block with clinical duration of action of 25-30 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 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 (suggested maintenance dose is 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 0.015 mg/kg dose under balanced anesthesia.
The recovery index (time from 25% to 75% recovery) is approximately 15-25 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. Rapid recovery is a finding consistent with vecuronium short elimination half-life, although there have been occasional reports of prolonged neuromuscular blockade in patients in the intensive care unit (See PRECAUTIONS).
The administration of clinical doses of vecuronium is not characterized by laboratory or clinical signs of chemically mediated histamine release. This does not preclude the possibility of rare hypersensitivity reactions (See ADVERSE REACTIONS).
At clinical doses of 0.04-0.10 mg/kg, 60-80% of vecuronium is usually bound to plasma protein. The distribution half-life following a single intravenous dose (range 0.025-0.280 mg/kg) is approximately 4 minutes. Elimination half-life over this same dosage range is approximately 65-75 minutes in healthy surgical patients and in renal failure patients undergoing transplant surgery.
In late pregnancy, elimination half-life may be shortened to approximately 35-40 minutes. The volume of distribution at steady state is approximately 300-400 mL/kg; systemic rate of clearance is approximately 3-4.5 mL/ minute/kg. In man, urine recovery of vecuronium varies from 3-35% within 24 hours. Data derived from patients requiring insertion of a T-tube in the common bile duct suggests that 25-50% 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 bromide 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 during 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.
Vecuronium Bromide Indications and Usage
Vecuronium bromide is indicated as an adjunct to general anesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.
Vecuronium bromide is contraindicated in patients known to have a hypersensitivity to it.
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. TO REDUCE THE POSSIBILITY OF PROLONGED NEUROMUSCULAR BLOCKADE AND OTHER POSSIBLE 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 WHO ARE FAMILIAR WITH APPROPRIATE PERIPHERAL NERVE STIMULATOR MUSCLE MONITORING TECHNIQUES (See PRECAUTIONS). 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 value in monitoring the response to administration of muscle relaxants.
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.
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.
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 Pharmacokinetics). Data currently available do not permit dosage recommendations in patients with impaired liver function.
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.
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.
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.
Vecuronium has no known effect on consciousness, the pain threshold or cerebration. Administration must be accompanied by adequate anesthesia or sedation.
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 0.04-0.06 mg/kg of vecuronium bromide may be administered to produce complete neuromuscular block with clinical duration of action of 25-30 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.
Use of volatile inhalational anesthetics such as enflurane, isoflurane, and halothane with vecuronium will enhance neuromuscular blockade. Potentiation is most prominent with use of enflurane and isoflurane. With the above agents the initial dose 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 CLINICAL PHARMACOLOGY).
Parenteral/intraperitoneal administration of high doses of certain antibiotics may intensify or produce 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, unexpected prolongation of neuromuscular block should be considered a possibility.
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 the neuromuscular blockade.
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